This invention pertains to a process for the preparation of alkyl esters of 1-methylcyclopropanecarboxylic acid. More specifically, this invention pertains to a process for the synthesis of alkyl 1-methylcyclopropanecarboxylates by a novel combination of steps starting with xcex3-butyrolactone.
The present invention is directed to an improved process for the production of alkyl esters of 1-methylcyclopropanecarboxylic acid. This method includes the preparation of a solution of an alkyl 4-halo-2-methyl butyrate in a solvent such as xylene with the purification and continuous removal of the alkyl ester of 1-methylcyllopropanecarboxylate as it is formed. The most common method used to form alkyl esters of 1-methylcyclopropane carboxylic acid involves carbene insertion into esters of xcex1-methylacrylic acid. For example, Siegel et. al. (J. Am. Chem. Soc, 1950, 72, pages 3815-3817) disclose the reaction of diazomethane with methyl methacrylate to produce methyl 1-methylcyclopropane carboxylate in a 63% yield. The tendency for diazomethane to explode limits its use on an industrial scale.
Cannon and coworkers (J. Am. Chem. Soc., 1959, 81, pages 1660-1666) disclose the reaction of xcex1-methyl-xcex3-chlorobutyric acid ethyl ester with sodamide under strictly anhydrous conditions in benzene to provide 1-methylcyclopropane carboxylic acid ethyl ester in a yield of 47.6%. Schwarze and coworkers, U.S. Pat. No. 4,520,209, disclose the reaction of methyl 4-chloro-2-methylbutyrate in methanol with an excess of sodium methylate at a reaction temperature of 90xc2x0 C. or higher. Although, an 87% yield was claimed by Schwarze et al., wiped film distillation or extraction was required to the separate methyl 1-methylcyclopropanecarboxylate from the sodium chloride by-product. Schwarze and coworkers disclose a boiling point for methyl 1-methylcyclopropanecarboxylate of 136xc2x0 C. German Patent Publication DE 3026094 discloses the conversion of 4-chloro-2-methylbutyrate to 1-methylcyclopropaneamide via sodium methoxide/ammonia in an autoclave at 145xc2x0 C.
There still exists a need for improved methods for the manufacture of alkyl esters of 1-methylcyclopropanecarboxylic acid. These esters are valuable intermediate products for the production of agrochemicals and pharmaceuticals. In particular alkyl esters of 1-methylcyclopropane carboxylic acid are useful intermediates for the manufacture of 1-methylcyclopropanecarboxamide and 1-methylcyclopropylamine.
The process provided by the present invention for the preparation of alkyl 1-methylcyclopropanecarboxylate comprises the steps of:
(1) contacting xcex3-butyrolactone with dimethylcarbonate in the presence of a basic catalyst to produce xcex1-methyl-xcex3-butyrolactone;
(2) contacting the xcex1-methyl-xcex3-butyrolactone from step (1) with a hydrogen halide in the presence of an alkanol to produce a reaction mixture containing an alkyl 4-halo-2-methylbutyrate;
(3) contacting the reaction mixture of step (2) with xylene to produce a xylene solution of an alkyl 4-halo-2-methylbutyrate;
(4) contacting the xylene solution of an alkyl 4-halo-2-methylbutyrate from step (3) with an alkali metal alkoxide under conditions of temperature and pressure which causes vaporization of (i) an alkanol as it is formed and (ii) an alkyl 1-methylcyclopropanecarboxylate as it is formed from the alkyl 4-halo-2-methylbutyrate.
The alkyl 1-methylcyclopropanecarboxylates obtained from our novel process may be converted to 1-methylcyclopropylamine by the steps of:
(5) contacting the alkyl 1-methylcyclopropanecarboxylate with an alkali metal hydroxide, carbonate or bicarbonate in the presence of water and a lower alkanol, e.g., an alkanol containing up to about 4 carbon atoms to produce an alkali metal 1-methyl cyclopropanecarboxylate;
(6) contacting the alkali metal 1-methylcyclopropanecarboxylate produced in step (5) with an acid to convert the alkali metal 1-methylcyclopropanecarboxylate to 1-methylcyclopropanecarboxylic acid;
(7) contacting the 1-methylcyclopropanecarboxylic acid produced in step (6) with thionyl chloride to convert the 1-methylcyclopropanecarboxylic acid to 1-methylcyclopropanecarbonyl chloride;
(8) contacting the 1-methyl cyclopropanecarbonyl chloride from step (7) with ammonia to convert the 1-methyl cyclopropanecarbonyl chloride to 1-methyl cyclopropanecarboxamide; and
(9) contacting the 1-methyl cyclopropanecarboxamide from step (8) with an alkali metal hydroxide and an alkali metal hypochlorite in the presence of water to convert the 1-methyl cyclopropanecarboxamide to 1-methyl cyclopropylamine.
A single-step embodiment of the present invention comprises the process of step (4) wherein an alkyl 1-methylcyclopropanecarboxylate is prepared and recovered by contacting a xylene solution of an alkyl 4-halo-2-methylbutyrate with an alkali metal alkoxide under conditions of temperature and pressure which causes vaporization of (i) an alkanol as it is formed and (ii) an alkyl 1-methylcyclopropanecarboxylate as it is formed from the alkyl 4-halo-2-methylbutyrate. 1-Methylcyclopropylamine is useful in the synthesis of antibacterial compounds described in U.S. Pat. No. 4,705,788.
The first step of the process is carried out by contacting xcex3-butyrolactone with dimethylcarbonate in the presence of a basic catalyst to produce xcex1-methyl-xcex3-butyrolactone. This reaction is described by M. Selva et al., J. Chem. Soc. Perkin Trans. 1; 1994, 1323, although methods for isolation of the product are not disclosed. In this step the dimethylcarbonate functions as both a solvent and reactant (methylating agent). Typically, the amounts of dimethylcarbonate and xcex3-butyrolactone employed give a dimethylcarbonate:xcex3-butyrolactone mole ratio in the range of about 1:1 to 20:1, preferably about 5:1 to 20:1. The first step may be carried out at a temperature in the range of about 160 to 250xc2x0 C., preferably about 200 to 240xc2x0 C. Especially preferred are reaction temperatures of about 210 to 240xc2x0 C. and reaction times of about 1 to 14 hours. Longer reaction times and higher temperatures permit the complete conversion of xcex3-butyrolactone which facilitates distillative purification of the produced xcex1-methyl-xcex3-butyrolactone. The reaction of xcex3-butyrolactone with dimethylcarbonate normally is carried out under super-atmospheric pressure, e.g., pressures in the range of about 27 to 90 bars absolute (baraxe2x80x94about 400 to 1300 pounds per square inchxe2x80x94psi). The basic catalyst employed in the first step may be selected from the alkali metal hydroxides, carbonate and bicarbonates, preferably the hydroxides and carbonates of sodium and potassium. Because of its solubility in the reaction mixture, potassium carbonate is the most preferred basic catalyst. The amount of basic catalyst used may be in the range of about 0.1 to 2 mole equivalents, preferably 0.5 to 2 mole equivalents, per mole of xcex3-butyrolactone reactant. Careful distillation will provide a product stream of xcex1-methyl-xcex3-butyrolactone in purities ranging between 90 and 100%. A high purity of xcex1-methyl-xcex3-butyrolactone minimizes problems with impurities in later steps.
In the second step of the process of the present invention, a solution of a hydrogen halide in an alkanol is added to the xcex1-methyl-xcex3-butyrolactone formed in step (1) to produce a reaction mixture containing an alkyl 4-halo-2-methylbutyrate. The preparation of methyl 4-chlorobutyrate and methyl cyclopropanecarboxylate from xcex3-butyrolactone is disclosed in U.S. Pat. No. 3,711,549 and references cited therein. The reaction of xcex1-methyl-xcex3-butyrolactone with HCl-saturated methanol for 24 hours followed by extraction into diethylether is disclosed by Ishikawa and coworkers, Chem. Pharm. Bull. 1995, 43, 2014. Because of its low boiling point and flammability, diethylether is not easily used on an industrial scale.
The hydrogen halide utilized in our novel process preferably is hydrogen bromide or, most preferably, hydrogen chloride. The amount of hydrogen halide used, e.g., either present in a hydrogen halide-saturated alkanol or fed to the alkanol solution of xcex1-methyl-xcex3-butyrolactone, is at least 1 mole per mole of xcex1-methyl-xcex3-butyrolactone, preferably about 2 to 10 moles hydrogen halide per mole of xcex1-methyl-xcex3-butyrolactone. The alkanol employed may contain up to about 4 carbon atoms but preferably is methanol. The amount of alkanol used typically give an alkanol: xcex1-methyl-xcex3-butyrolactone mole ratio of about 20:1 to 2:1, preferably about 10:1 to 5:1. The second step may be carried out at a temperature in the range of about 0 to 100xc2x0 C., preferably about 25 to 60xc2x0 C. Pressure is not important in the operation of step (2) and therefore pressures moderately above or below ambient pressure may be used. The first and second steps of our novel process normally should be carried out under anhydrous or substantially anhydrous conditions which is defined herein as less than 10 weight percent water. It is preferred that less than 5% water be present at the end of reaction.
In the third step of the process, the reaction mixture from step (2) is contacted with xylene to produce a xylene solution of an alkyl 4-halo-2-methylbutyrate. This xylene extraction of the alkyl 4-halo-2-methylbutyrate may be accomplished by intimately contacting a mixture of xylene and water with the reaction mixture from step (2). The amount of xylene typically employed in this step is about 1 to 50 parts by weight xylene per part by weight alkyl 4-halo-2-methylbutyrate present in the step (2) reaction mixture. Water may be present in the xylene-extraction mixture in amounts which give xylene:water weight ratios of about 1:0 to 1:10, preferably about 1:0 to 1:1. The extraction of step (3) may by performed at temperatures in the range of about xe2x88x9210 to 30xc2x0 C., preferably about 0 to 25xc2x0 C. Step (3) typically produces solutions comprising about 10 to 50 weight percent alkyl 4-halo-2-methylbutyrate in xylene. Any water present in the xylene solution normally is removed from the xylene solution of the alkyl 4-halo-2-methylbutyrate by azeotropic distillation to produce a substantially anhydrous xylene solution for use in step (4). Other hydrocarbons which may be used in the third step of our novel process include those with a boiling point equal to or higher than that of xylene and include naphthalene, methyinaphthalene and mesitylene. Because of its availability and favorable properties including boiling point, water azeotrope and solubility for alkyl 4-halo-2-methylbutyrate, xylene is especially preferred. The xylene may be o-, m-, or p-xylene, or ethylbenzene or may be a mixture of 2, 3 or all 4 xylene isomers.
In the fourth step of our novel process, the xylene solution of an alkyl 4-halo-2-methylbutyrate from step (3) is contacted with an alkali metal alkoxide under substantially anhydrous conditions to produce an alkyl 1-methylcyclopropanecarboxylate. We are aware of two reports of the generation of alkyl 1-methylcyclopropylcarboxylates from alkyl 4-chloro-2-methylbutyrates. Cannon et al., J. Am. Chem. Soc. 1959, 81, 1660, report the reaction of sodamide with ethyl 4-chloro-2-methylbutyrate under strictly anhydrous conditions in benzene to give ethyl 1-methyl-cycloproanecarboxylate in 47.6% yield. As noted above Schwarze and coworkers, U.S. Pat. No. 4,520,209, disclose the reaction of methyl 4-chloro-2-methylbutyrate in methanol with an excess of sodium methylate at a reaction temperature of 90xc2x0 C. or higher and the separation of methyl 1-methylcyclopropanecarboxylate from the sodium chloride by-product using wiped film distillation or extraction.
The fourth step of the present process is performed under conditions of temperature and pressure which cause or result in the vaporization of (i) an alkanol as it is formed and (ii) an alkyl 1-methylcyclopropanecarboxylate as it is formed from the alkyl 4-halo-2-methylbutyrate. For example, the azeotropically-dried xylene solution containing methyl 4-chloro-2-methylbutyrate may be added directly to a solution of sodium methoxide in xylene and the product methyl 1-methylcyclopropanecarboxylate may be distilled directly from this reaction mixture. This technique has the advantage of retaining the co-produced sodium chloride in the undistilled xylene (bp 136-142xc2x0 C.) while the product is removed (observed bp ca. 125-130xc2x0 C.). The use of xylene also permits the rapid removal of methanol as it is formed from the reaction of sodium methoxide and methyl 4-chloro-2-methylbutyrate.
The alkoxide moiety of alkali metal alkoxides used in the fourth step may contain up to about 4 carbon atoms but preferably is a methoxide or ethoxide residue. The alkali metal preferably is sodium or potassium. The amount of alkali metal alkoxide used normally is at least one mole per mole of alkyl 4-chloro-2-methylbutyrate reactant. The amount of alkali metal alkoxide used preferably is about 1 to 1.3 moles of alkali metal alkoxide per mole of alkyl 4-chloro-2-methylbutyrate reactant. In a preferred mode of operation, the azeotropically-dried xylene solution containing the alkyl 4-chloro-2-methylbutyrate is added directly to a solution of the alkali metal alkoxide in xylene. Step (4) is carried out at a temperature in the range of about 100 to 200xc2x0 C. to first vaporize by-product alkanol derived from the alkali metal alkoxide and then to vaporize the alkyl 1-methylcyclopropanecarboxylate as it is formed from the intermediate alkali salt of alkyl 4-halo-2-methylbutyrate. Pressure is not an important feature of step (4) and therefore pressures moderately above or below ambient pressure may be used.
The use of the preferred reactants and conditions is the basis for a preferred embodiment of the present invention for the preparation of methyl 1-methylcyclopropanecarboxylate which comprises the steps of:
(1) contacting xcex3-butyrolactone with dimethylcarbonate in the presence of a basic catalyst to produce xcex1-methyl-xcex3-butyrolactone;
(2) contacting the xcex1-methyl-xcex3-butyrolactone from step (1) with hydrogen chloride in the presence of methanol to produce a reaction mixture containing methyl 4-chloro-2-methylbutyrate;
(3) contacting the reaction mixture of step (2) with xylene to produce a substantially anhydrous xylene solution of methyl 4-chloro-2-methylbutyrate; and
(4) contacting the xylene solution of methyl 4-chloro-2-methylbutyrate from step (3) with an sodium methoxide and heating at temperatures of about 100 to 200xc2x0 C. which causes vaporization of (i) methanol as it is formed and (ii) methyl 1-methylcyclopropanecarboxylate as it is formed from methyl 4-chloro-2-methylbutyrate.
The alkyl 1-methylcyclopropanecarboxylate esters obtained from the process of our invention may be converted to 1-methylcyclopropylamine by the additional steps of:
(5) contacting the alkyl 1-methylcyclopropanecarboxylate produced in step (4) with an alkali metal hydroxide, carbonate or bicarbonate in the presence of water and a lower alkanol, e.g., an alkanol containing up to about 4 carbon atoms to produce an alkali metal 1-methylcyclopropanecarboxylate;
(6) contacting the alkali metal 1-methylcyclopropanecarboxylate produced in step (5) with an acid to convert the alkali metal 1-methylcyclopropanecarboxylate to 1-methylcyclopropanecarboxylic acid;
(7) contacting the 1-methylcyclopropanecarboxylic acid produced in step (6) with thionyl chloride to convert the 1-methylcyclopropanecarboxylic acid to 1-methylcyclopropanecarbonyl chloride;
(8) contacting the 1-methyl cyclopropanecarbonyl chloride from step (7) with ammonia to convert the 1-methylcyclopropanecarbonyl chloride to 1-methylcyclopropanecarboxamide; and
(9) contacting the 1-methylcyclopropanecarboxamide from step (8) with an alkali metal hydroxide and an alkali metal hypochlorite in the presence of water to convert the 1-methyl cyclopropanecarboxamide to 1-methylcyclopropylamine.
As shown by the examples set forth below, two or more of steps (5)-(9) may be carried out in the same reactor without isolation of the intermediate compound. The 1-methyl cyclopropylamine produced in step (9) may be contacted with a mineral acid such as a hydrogen halide or sulfuric acid to convert the 1-methyl cyclopropylamine to its addition salt, e.g., 1-methyl cyclopropylamine hydrochloride or sulfate.
Step (5) comprises contacting the alkyl 1-methylcyclopropanecarboxylate produced in step (4) with a base selected from alkali metal hydoxide, carbonate or bicarbonate in the presence of water and a lower alkanol, e.g., an alkanol containing up to about 4 carbon atoms to produce an alkali metal 1-methyl cyclopropanecarboxylate. The base utilized in step (5) preferably is an alkali metal hydroxide, most preferably sodium or potassium hydroxide. The amount of base used normally will provide one equivalent, preferably 1 to 1.5 equivalents, of base per mole of alkyl 1-methylcyclopropanecarboxylate. The saponification of step (5) may be carried out at a temperature in the range of about 0 to 120xc2x0 C., preferably about 25 to 80xc2x0 C. Step (5) preferably is carried out by (i) mixing a solution of alkyl 1-methylcyclopropanecarboxylate in xylene produced in step (4) with a base selected from alkali metal hydroxide, carbonate or bicarbonate in the presence of water and a lower alkanol; (ii) heating the mixture to convert the alkyl 1-methylcyclopropanecarboxylate to an alkali metal 1-methylcyclopropanecarboxylate; (iii) allowing the reaction mixture to separate into an organic phase and an aqueous phase; and recovering the aqueous phase for step (6). Normally, the alkanol used in step (5) is removed from the aqueous phase prior to the step (6) acidification.
Step (6) comprises contacting the alkali metal 1-methylcyclopropanecarboxylate produced in step (5) with an acid in the presence of water to convert the alkali metal 1-methylcyclopropanecarboxylate to 1-methylcyclopropanecarboxylic acid. Examples of acids which may be used include the hydrogen halides such hydrochloric and hydrobromic acid and sulfuric acid. The amount of acid used usually will be about one equivalent, preferably about 1 to 1.5 equivalents, of acid per mole of alkali metal 1-methylcyclopropanecarboxylate. Step (6) may be carried out at a temperature in the range of about 0 to 100xc2x0 C., preferably about 25 to 70xc2x0 C. Upon completion of the reaction, the reaction mixture separates into two phases comprising an aqueous phase and an organic phase comprising the 1-methylcyclopropanecarboxylic acid product. An inert (non-reactive) hydrocarbon solvent such as toluene may be added to the reaction mixture to dilute/dissolve the 1-methylcyclopropanecarboxylic acid product followed by separation of the organic phase comprising a solution of the acid product in hydrocarbon solvent. This organic phase normally is heated to remove by distillation any water present, i.e., water dissolved in the organic phase.
In step (7) the 1-methylcyclopropanecarboxylic acid produced in step (6) is contacted with with thionyl chloride to convert the 1-methylcyclopropanecarboxylic acid to 1-methylcyclopropanecarbonyl chloride. The amount of thionyl chloride used usually will about one mole, preferably about 1 to 1.5 moles, of thionyl chloride per mole of 1-methylcyclopropanecarboxylic acid. Step (7) may be carried out at a temperature in the range of about 0 to 100xc2x0 C., preferably about 50 to 90xc2x0 C. This step is carried out in the presence of an inert organic solvent, preferably the hydrocarbon solvent used in step (6) to dilute/dissolve the 1-methylcyclopropanecarboxylic acid product. The reaction mixture comprising 1-methylcyclopropanecarbonyl chloride dissolved in a hydrocarbon solvent may be used in the next step without further treatment.
Step (8) comprises contacting the 1-methyl cyclopropanecarbonyl chloride from step (7) with ammonia, e.g., aqueous ammonium hydroxide, in the presence of an inert hydrocarbon solvent to convert the 1-methylcyclopropanecarbonyl chloride to 1-methylcyclopropanecarboxamide. The amount of ammonia used usually will be about one mole, preferably about 1 to 10 moles, of ammonia per mole of 1-methylcyclopropanecarbonyl chloride. Step (8) may be carried out at a temperature in the range of about xe2x88x9210 to 50xc2x0 C., preferably about 0 to 20xc2x0 C. Upon completion of the reaction and cooling of the crude reaction mixture, e.g., to 0-5xc2x0 C., the amide product precipitates and may be collected by filtration.
In step (9), 1-methyl cyclopropanecarboxamide from step (8) is contacted with an alkali metal hydroxide and an alkali metal hypochlorite, e.g. sodium hypochlorite, in the presence of water to convert the 1-methylcyclopropanecarboxamide to 1-methylcyclopropylamine. The alkali metal hydroxide preferably is potassium or, most preferably, sodium hydroxide. The amount of alkali metal hydroxide employed on step (9) typically is about one mole, preferably about 2 to 6 moles, of alkali metal hydroxide per mole of 1-methylcyclopropanecarboxamide. The amount of alkali metal hypochlorite, e.g., sodium hypochlorite, used typically is about one mole, preferably about 1 to 1.5 moles, of alkali metal hypochlorite per mole of 1-methylcyclopropanecarboxamide. Step (9) may be carried out at a temperature in the range of about xe2x88x925 to 100xc2x0 C., preferably about 0 to 80xc2x0 C. Any unreacted alkali metal hypochlorite may be decomposed by the addition of sodium thiosulfate and then the 1-methylcyclopropylamine product may be recovered as a mixture with water by simple distillation or in greater than 98% purity by fractional distillation. As mentioned above, the 1-methylcyclopropylamine may be contacted with a mineral acid such as a hydrogen halide or sulfuric acid to convert the 1-methyl cyclopropylamine to its addition salt, e.g., 1-methylcyclopropylamine hydrochloride or sulfate.